Clinical Management of Multidrug-Resistant Tuberculosis in 16 European Countries.

RATIONALE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. OBJECTIVES: To document the management and treatment outcome in patients with MDR-TB in Europe. METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). MEASUREMENTS AND MAIN RESULTS: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%). CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

[Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. / S2k-Leitlinie: Tuberkulose im Erwachsenenalter.

Since 2015 a significant increase in tuberculosis cases is notified in Germany, mostly due to rising numbers of migrants connected to the recent refugee crisis. Because of the low incidence in previous years, knowledge on tuberculosis is more and more limited to specialized centers. However, lung specialist and healthcare workers of other fields have contact to an increasing number of tuberculosis patients. In this situation, guidance for the management of standard therapy and especially for uncommon situations will be essential. This new guideline on tuberculosis in adults gives recommendations on diagnosis, treatment, prevention and prophylaxis. It provides a comprehensive overview over the current knowledge, adapted to the specific situation in Germany. The German Central Committee against Tuberculosis (DZK e. V.) realized this guideline on behalf of the German Respiratory Society (DGP). A specific guideline for tuberculosis in the pediatrics field will be published separately. Compared to the former recommendations of the year 2012, microbiological diagnostics and therapeutic drug management were given own sections. Chapters about the treatment of drug-resistant tuberculosis, tuberculosis in people living with HIV and pharmacological management were extended. This revised guideline aims to be a useful tool for practitioners and other health care providers to deal with the recent challenges of tuberculosis treatment in Germany.

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.

Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection.

Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the under-lying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4⁺ T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-γ. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-γ expressing, ESAT-6 specific CD4⁺CD45RO⁺CD27⁻ T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions.

Loss of T cells expressing CD27 at the site of active tuberculosis - A prospective diagnostic study.

The lack of a rapid and reliable diagnostic test for active tuberculosis is still a burden to the control of the infection. The accumulation of Mycobacterium tuberculosis (MTB)-specific CD4+ T cells at the site of infection and the increase of MTB-specific CD27- cells seem to be characteristic for active tuberculosis. We evaluated CD27 expression of non-stimulated T cells at the site of infection compared to peripheral blood of seventy-two patients (n = 72) presenting with symptoms of active MTB-infection. Twenty patients (n = 20, 27.8%) were actually confirmed to have active tuberculosis. Overall, a significant increase of terminally differentiated CD27- CD4+ T cells at the site of disease was noted when compared to peripheral blood (<0.001). However, the loss of CD27 at the site of disease was not restricted to active tuberculosis (p = 0.253). The CD27 expression profile of tuberculosis patients was only discriminative to patients with malignancy.

High Rates of Treatment Success in Pulmonary Multidrug-Resistant Tuberculosis by Individually Tailored Treatment Regimens.

RATIONALE: We evaluated whether treatment outcomes for patients with multidrug-resistant and extensively drug-resistant tuberculosis can be substantially improved when sufficient resources for personalizing medical care are available. OBJECTIVES: To describe the characteristics and outcomes of patients with pulmonary multidrug-resistant tuberculosis at the Otto Wagner Hospital in Vienna, Austria. METHODS: We conducted a retrospective single-center study of patients initiated on treatment for multi-drug resistant tuberculosis between January 2003 and December 2012 at the Otto Wagner Hospital, Vienna, Austria. The records of patients with multidrug-resistant tuberculosis were reviewed for epidemiological, clinical, laboratory, treatment, and outcome data. MEASUREMENTS AND MAIN RESULTS: Ninety patients with pulmonary multidrug-resistant tuberculosis were identified. The median age was 30 years (interquartile range, 26-37). All patients were of non-Austrian origin, and 70 (78%) came from former states of the Soviet Union. Thirty-nine (43%) patients had multidrug-resistant tuberculosis; 28 (31%) had additional bacillary resistance to at least one second-line injectable drug and 9 (10%) to a fluoroquinolone. Fourteen (16%) patients had extensively drug-resistant tuberculosis. Eighty-eight different drug combinations were used for the treatment of the 90 patients. Surgery was performed on 10 (11.1%) of the patients. Sixty-five (72.2%) patients had a successful treatment outcome, 8 (8.9%) defaulted, 3 (3.3%) died, 8 (8.9%) continued treatment in another country and their outcome was unknown, and 6 (6.7%) were still on therapy. None of the patients experienced treatment failure. Treatment outcomes for patients with extensively drug-resistant tuberculosis were similar to those of patients with multidrug-resistant tuberculosis. CONCLUSIONS: High rates of treatment success can be achieved in patients with multidrug-resistant and extensively drug-resistant tuberculosis when individually tailored treatment regimens can be provided in a high-resource setting.

Peripheral T cell cytokine responses for diagnosis of active tuberculosis.

BACKGROUND: A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients. METHODS: Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) T cells and CD8(+) T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively. RESULTS: Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+) T cell derived interferon (IFN)-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases. CONCLUSION: T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a "memory type" to an "effector type" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.

Catheter-related Leuconostoc bacteremia secondary to pulmonary Mycobacterium xenopi infection.

Infection caused by Leuconostoc spp. is very rare. We report a case of Leuconostoc bacteremia in a patient receiving antimycobacterial chemotherapy for pulmonary Mycobacterium xenopi infection. In addition, the patient presented several known characteristic predisposing factors associated with Leuconostoc infection, such as severe underlying disease, previous long-term antibiotic treatment, indwelling intravascular catheter, prolonged parenteral feeding, previous methicillin-resistant Staphylococcus epidermidis (MRSE) bacteremia with subsequent vancomycin treatment, and prolonged hospitalization. Leuconostoc spp. were isolated from several blood cultures and from a retracted intravascular catheter. After removal of the intravascular catheter the patient's condition improved without additional antibiotic treatment. To our knowledge, this is the first report of a patient with Leuconostoc spp. infection secondary to pulmonary non-tuberculous mycobacteriosis.